2018 Section 5 - Rhinology and Allergic Disorders

Reprinted by permission of J Allergy Clin Immunol. 2015; 136(6):1442-1453.

Mechanisms of allergic diseases

Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

Chronic rhinosinusitis pathogenesis

Whitney W. Stevens, MD, PhD, a * Robert J. Lee, PhD, b,c * Robert P. Schleimer, PhD, a,d and Noam A. Cohen, MD, PhD b,e,f Chicago, Ill, and Philadelphia, Pa

There are a variety of medical conditions associated with chronic sinonasal inflammation, including chronic rhinosinusitis (CRS) and cystic fibrosis. In particular, CRS can be divided into 2 major subgroups based on whether nasal polyps are present or absent. Unfortunately, clinical treatment strategies for patients with chronic sinonasal inflammation are limited, in part because the underlying mechanisms contributing to disease pathology are heterogeneous and not entirely known. It is hypothesized that alterations in mucociliary clearance, abnormalities in the sinonasal epithelial cell barrier, and tissue remodeling all contribute to the chronic inflammatory and tissue-deforming processes characteristic of CRS. Additionally, the host innate and adaptive immune responses are also significantly activated and might be involved in pathogenesis. Recent advancements in the understanding of CRS pathogenesis are highlighted in this review, with special focus placed on the roles of epithelial cells and the host immune response in patients with cystic fibrosis, CRS without nasal polyps, or CRS with nasal polyps. (J Allergy Clin Immunol 2015;136:1442-53.) Key words: Chronic rhinosinusitis, nasal polyps, mucociliary clearance, epithelial cells, inflammation, microbiome From a the Division of Allergy-Immunology, Department of Medicine, d the Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago; b the Departments of Otorhinolaryngology–Head and Neck Surgery and c Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; e the Philadel- phia Veterans Affairs Medical Center, Surgical Service; and f the Monell Chemical Senses Center, Philadelphia. Some of the research described in this review and effort directed towards writing the review was supported by USPHS grants R01DC013588, R21DC013886 (to N.A.C.), and R03DC013862 (to R.J.L.); National Institutes of Health grants T32 AI083216 and R01 AI104733 (to R.P.S.); the Ernest S. Bazley Foundation (to R.P.S.); the Chronic Rhinosinusitis Integrative Studies Program U19-AI106683 (to R.P.S.), and a philan- thropic contribution from the RLG Foundation (to N.A.C.). Disclosure of potential conflict of interest: R. J. Lee has received a grant from the National Institutes of Health (NIH). R. P. Schleimer has received grants from the NIH; has consultant arrangements with Intersect ENT, GlaxoSmithKline, Allakos, Aur- asense, Merck, BioMarck, and Sanofi; and has stock/stock options with Allakos, Aurasense, and BioMarck. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication September 29, 2015; revised October 21, 2015; accepted for publication October 21, 2015. Corresponding author: Robert P. Schleimer, PhD, Division of Allergy-Immunology, 240 E Huron St, McGaw Rm M-318, Chicago, IL 60611. E-mail: rpschleimer@ northwestern.edu . 0091-6749/$36.00 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.10.009 Terms in boldface and italics are defined in the glossary on page 1443. *These authors contributed equally to this work. These authors contributed equally to this work.

Abbreviations used

ASL: Airway surface liquid CF: Cystic fibrosis CFTR: Cystic fibrosis transmembrane conductance regulator CRS: Chronic rhinosinusitis

CRSsNP: Chronic rhinosinusitis without nasal polyps CRSwNP: Chronic rhinosinusitis with nasal polyps MCC: Mucociliary clearance NO: Nitric oxide NOS: Nitric oxide synthase PAMP: Pathogen-associated molecular pattern T2R: Taste family type 2 receptor Treg: Regulatory T UT: Uncinate tissue

Chronic rhinosinusitis (CRS) is characterized by chronic inflammation of the sinonasal mucosa and clinically associated with sinus pressure, nasal congestion, rhinorrhea, and a decreased sense of smell persisting for greater than 12 weeks. 1 CRS can be subdivided into 2 major categories based on whether nasal polyps are present (chronic rhinosinusitis with nasal polyps [CRSwNP]) or absent (chronic rhinosinusitis without nasal polyps [CRSsNP]). 2 Although CRS is estimated to affect more than 10 million patients in the United States and leads to $22 billion in total annual costs, 1,3 there are other diseases, such as cystic fibrosis (CF), that also involve chronic sinonasal inflammation and nasal polyp formation that have important clinical implications. A better understanding of CRS pathogenesis is needed to advance the current diagnostic and treatment strategies available for affected patients. THE SINONASAL MICROBIOME Much like the gut, the sinonasal cavity has a resident flora that maintains an environment conducive to respiratory health. Sub- stantial effort has recently been made using culture-independent techniques (ie, molecular diagnostics) to attempt to understand and define the microbial community or microbiome of the human sinonasal cavity in the healthy and diseased (CRS) states. 4-10 No consistent patterns have emerged in the diseased state to implicate a specific organism or organisms as causative, but data suggest an imbalance (or dysbiosis) is found in patients with CRS with a decrease in microbial diversity. Another concept that has emerged is that the correct balance of microbes within the local microbiome might be immunomodulatory and that an imbalance shifts an important regulator of local inflammation. 11 Puzzles that remain include the existence of similar microbial species in

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